title: Buddlejasaponin IV induces cell cycle arrest at G2/M phase and apoptosis in immortalized human oral keratinocytes.
abstract: Buddlejasaponin IV (BS-IV), a major component of Pleurospermum kamtschaticum, exerts antiinflammatory and cytotoxic effects against cancer cells. The study investigated whether BS-IV could prevent oral carcinogenesis by inhibiting the growth of immortalized human oral keratinocytes (IHOKs). BS-IV reduced cell viability and induced cell cycle arrest at G2/M phase and apoptotic morphological changes in IHOKs. BS-IV inhibited the levels of cyclin B1, Cdc2 and Cdc25C, but enhanced Chk2 phosphorylation. The increased levels of pRb and p21 protein and the activation of p53 were also noted in BS-IV-treated IHOKs. In addition, BS-IV induced cytochrome c release from mitochondria by reducing antiapoptotic Bcl-2 levels and increasing pro-apoptotic Bax levels. BS-IV treatment resulted in the activation of caspase-9 and caspase-3. PARP cleavage was also clearly observed in the BS-IV-treated IHOKs. Furthermore, the expression of the Fas death receptor and Fas ligand was induced and procaspase-8 level was suppressed by BS-IV treatment. Taken together, BS-IV treatment inhibited the growth of IHOK cells via the induction of p53-dependent cell cycle arrest at the G2/M phase and apoptosis via both mitochondrial-dependent and death receptor-mediated pathways. Thus, BS-IV can be considered an excellent candidate for a chemopreventive agent to block the progression of HPV-induced oral carcinogenesis.
authors.affiliation: Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Korea.
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Hwang
authors.forename: Won-Yoon
authors.initials: WY
authors.lastname: Chung
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: Hee-Juhn
authors.initials: HJ
authors.lastname: Park
authors.forename: Eun-Cheol
authors.initials: EC
authors.lastname: Kim
authors.forename: Kwang-Kyun
authors.initials: KK
authors.lastname: Park
mesh_terms: D052685:Alphapapillomavirus; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D019661:Apiaceae / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000517:prevention & control / Q000821:virology; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009061:Mouth Mucosa / Q000187:drug effects* / Q000378:metabolism; D009062:Mouth Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000821:virology; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D055273:Salivary Proline-Rich Proteins / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology* / Q000627:therapeutic use; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D048069:Tumor Necrosis Factors / Q000378:metabolism; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C524744:PRB1 protein, human; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D055273:Salivary Proline-Rich Proteins; D012503:Saponins; D014315:Triterpenes; D048069:Tumor Necrosis Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C418227:buddlejasaponin IV; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases